Synthesis of Heteroaromatic Compounds: Indoles and 6-Membered Rings
In this section, we will see the synthesis of other types heteroaromatics which are indoles and 6-membered rings. Unsurprisingly, those classes of heteroaromatics are common in the organic compounds such as in pharmaceutical and in natural products.
This syntheses will be carried in the same principles as the 5-membered ring heteroaromatics, which is carbonyl chemistry.
Indole is an 5-membered N-heteroaromatic ring fused to a benzene ring and indole can be synthesised from a carbonyl compound and phenylhydrazine.
The reaction proceeds via:
This synthesis is known as Fischer indole synthesis because it was developed by Emil Fischer. This reaction is also used to synthesise sumatriptan which is an analogue of serotonin and it is used for migraine treatment.
The use of acetal is to avoid self-condensation due to the reactive nature of aldehyde.
Another reaction to synthesise indole is called Reissert synthesis, which uses 2-nitrotoluene as starting material.
Now, we can move to the synthesis of 6-membered ring and we start from pyridine. Pyridine can be synthesised from 1,5-dicarbonyl compound with ammonia as shown below.
However, there is a problem of the oxidation level of ring which requires oxidation step using air or DDQ (dichlorodicyanoquinone). This problem can be overcome by reacting with H2NOH, instead of ammonia.
The reaction proceeds via:
The use of H2NOH allows aromatisation by loss of water; hence no need for oxidising agent. Furthermore, 1,5-dicarbonyls can be made from reaction between enamine and conjugated carbonyl compound.
Another way to synthesise 6-membered ring pyridine is Hantzsch pyridine synthesis which was developed by Arthur Hantzsch.
The reaction proceeds via:
The other two 6-membered rings are pyridazines which can be made from 1,4-dicarbonyl and hydrazine followed by oxidation, and pyrimidines can be made from 1,3-dicarbonyl and amidines.
The other types of heteroaromatic compounds are quinolines and isoquinolines, where a pyridine ring is fused to benzene ring.
There are 2 ways to synthesise quinoline and the first reaction is called Skraup reaction.
The reaction proceeds via:
This reaction is known as the worst 'witch's brew' of heteroaromatic synthesis because some workers add strange oxidising agent such as arsenic acid, iron(III) salts, tin(IV) salts, nitrobenzenes of various substitution patterns, or iodine to make it go better.
Another way to synthesise quinolines is using Friedlander synthesis and this reaction proceeds via enamines followed by dehydration.
Meanwhile, isoquinoline is also have two ways to synthesise and firstly is Bischler-Napieralski reaction proceeds via amide formation.
The cyclisation proceeds via:
The Bischler-Napieralski is used in the synthesis of papaverine which is a coronary vasodilator and it is an alkaloid from opium. The synthesis of papaverine is shown below.
Isoquinoline can also be synthesised via Pictet-Spengler reaction and this reaction proceeds via imine instead of amide.
The intermediate tetrahydroisoquinoline can be oxidised to isoquinoline using mild oxidising agent.
Indole is an 5-membered N-heteroaromatic ring fused to a benzene ring and indole can be synthesised from a carbonyl compound and phenylhydrazine.
Another reaction to synthesise indole is called Reissert synthesis, which uses 2-nitrotoluene as starting material.
Now, we can move to the synthesis of 6-membered ring and we start from pyridine. Pyridine can be synthesised from 1,5-dicarbonyl compound with ammonia as shown below.
Another way to synthesise 6-membered ring pyridine is Hantzsch pyridine synthesis which was developed by Arthur Hantzsch.
The other two 6-membered rings are pyridazines which can be made from 1,4-dicarbonyl and hydrazine followed by oxidation, and pyrimidines can be made from 1,3-dicarbonyl and amidines.
The other types of heteroaromatic compounds are quinolines and isoquinolines, where a pyridine ring is fused to benzene ring.
Another way to synthesise quinolines is using Friedlander synthesis and this reaction proceeds via enamines followed by dehydration.
Meanwhile, isoquinoline is also have two ways to synthesise and firstly is Bischler-Napieralski reaction proceeds via amide formation.
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